Popular antidepressants including Prozac and Paxil have little impact on most patients, according to a comprehensive review of newly released data from trials that were conducted before the drugs were
approved in the U.S.

Researchers from the U.K., U.S. and Canada analyzed results for
fluoxetine (better known by the brand name Prozac), venlafaxine (Effexor),
nefazodone (Serzone) and paroxetine (Paxil or Seroxat)  all members of a
class of drugs known as selective serotonin reuptake inhibitors (SSRIs). The
researchers' paper, published this week in the journal PLoS Medicine,
claims that only patients who are diagnosed "at the upper end of the very
severely depressed category" get any meaningful benefit from the widely
prescribed drugs. For the others, the paper says, antidepressants are barely
more effective than a placebo (although patients suffering from depression, like those suffering from chronic pain, generally do see a substantial placebo benefit).

There are plenty of studies about antidepressants. What makes this one so
important  the results were front-page news across the U.K. on Tuesday  is that the researchers were able to track down comprehensive unpublished
trial results from the drug makers themselves before the drugs were authorized for sale in the U.S.,
and include them in their review of the literature. The U.S. Food and Drug
Administration (FDA) must receive records of all relevant pharmaceutical-company trials, both published
and unpublished, before it will approve a drug. Under the Freedom of
Information Act, the researchers writing in PLoS Medicine were
recently able to obtain those FDA records of industry-sponsored clinical trials. They yield data, they believe, that
lets them avoid a bias that often plagues reviews of previous research: the
tendency for conclusive positive results to be published, sometimes more
than once, and thus over-represented, while mediocre results can be ignored
or even swept under the rug.

Drug companies claim the review is still flawed, however. One massive
problem: there are many more recent studies than those surveyed in the
article, which looked only at pre-approval trials conducted before 1999.
Nicholas Francis, a U.K. spokesman for Eli Lilly and Company, which produces
Prozac, says that the new study "does not take into account that today more than 12,000 patients have participated in Prozac
clinical trials and thousands of scientific papers have referenced Prozac,
supporting its use in the treatment of depression." Some 50 million people
worldwide have taken Prozac, and in a company statement Lilly said it "is
proud of the difference Prozac has made to millions of people living with
depression." Similarly, paroxetine producer GlaxoSmithKline warns, "This
analysis has only examined a small subset of the total data available ...
and this one study should not be used to cause unnecessary alarm and concern
for patients." As a spokeswoman for Wyeth, Effexor's maker, points out,
these were, after all, the same data the FDA reviewed before
approving the drugs for public use.

There are really two issues at the heart of the controversy. One is the
difference between "statistical significance"  a measure of whether the
drug's effects are reliable, and that patient improvement is not just due to
chance  and "clinical significance," whether those effects actually are
big enough to make a difference in the life of a patient. The researchers behind this new paper did find that SSRI drugs have a
statistically significant impact for most groups of patients: that is, there
was some measurable impact on depression compared to the placebo effect.
"But a very tiny effect may not have a meaningful difference in a person's
life," says Irving Kirsch, lead author on the paper and a professor of
psychology at the University of Hull in England. As it happens, only for the
most severely depressed patients did that measurable difference meet a U.K.
standard for clinical relevance  and that was mostly because the very depressed did not respond as much to placebos. The drug trials showed SSRI patients improved, on average, by 1.8 points on the Hamilton Depression Rating Scale, a common tool to rate symptoms such as low mood, insomnia, and lack of appetite. The U.K. authorities use a drug-placebo difference of three points to determine clinical significance.

The more troubling question concerns what kind of data is appropriate
for analyzing a drug's efficacy. The companies are correct in claiming there
is far more data available on SSRI drugs now than there was 10 or 20 years
ago. But Kirsch maintains that the results he and colleagues reviewed make
up "the only data set we have that is not biased." He points out that
currently, researchers are not compelled to produce all results to an
independent body once the drugs have been approved; but until they are, they
must hand over all data. For that reason, while the PLoS Medicine
paper data may not be perfect, it may still be among the best we've got.